| Literature DB >> 35021065 |
Nitish Rana1, Giuseppe Privitera2, Hannah C Kondolf2, Katarzyna Bulek3, Susana Lechuga3, Carlo De Salvo2, Daniele Corridoni4, Agne Antanaviciute4, Rebecca L Maywald5, Alexander M Hurtado2, Junjie Zhao3, Emina H Huang6, Xiaoxia Li3, E Ricky Chan7, Alison Simmons4, Giorgos Bamias8, Derek W Abbott2, Jason D Heaney5, Andrei I Ivanov3, Theresa T Pizarro9.
Abstract
Gasdermins are a family of structurally related proteins originally described for their role in pyroptosis. Gasdermin B (GSDMB) is currently the least studied, and while its association with genetic susceptibility to chronic mucosal inflammatory disorders is well established, little is known about its functional relevance during active disease states. Herein, we report increased GSDMB in inflammatory bowel disease, with single-cell analysis identifying epithelial specificity to inflamed colonocytes/crypt top colonocytes. Surprisingly, mechanistic experiments and transcriptome profiling reveal lack of inherent GSDMB-dependent pyroptosis in activated epithelial cells and organoids but instead point to increased proliferation and migration during in vitro wound closure, which arrests in GSDMB-deficient cells that display hyper-adhesiveness and enhanced formation of vinculin-based focal adhesions dependent on PDGF-A-mediated FAK phosphorylation. Importantly, carriage of disease-associated GSDMB SNPs confers functional defects, disrupting epithelial restitution/repair, which, altogether, establishes GSDMB as a critical factor for restoration of epithelial barrier function and the resolution of inflammation.Entities:
Keywords: FAK; GSDMB; GSDMB genetic polymorphisms; Mtx; PDGFA; epithelial organoids; epithelial restitution and repair; focal adhesion kinase; gasdermin B; gasdermins; inflammatory bowel disease; intestinal epithelial cells; methotrexate; platelet-derived growth factor A; resolution of inflammation; single-cell RNA-seq; single-cell profiling
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Year: 2022 PMID： 35021065 PMCID： PMC8879997 DOI： 10.1016/j.cell.2021.12.024
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582